Targeted imaging of matrix metalloproteinase activity in the evaluation of remodeling tissue-engineered vascular grafts implanted in a growing lamb model

Objectives: The clinical translation of tissue-engineered vascular grafts has been demonstrated in children. The remodeling of biodegradable, cell-seeded scaffolds to functional neovessels has been partially attributed to matrix metalloproteinases. Noninvasive assessment of matrix metalloproteinase activity can indicate graft remodeling and elucidate the progression of neovessel formation. Therefore, matrix metalloproteinase activity was evaluated in grafts implanted in lambs using in vivo and ex vivo hybrid imaging. Graft growth and remodeling was quantified using in vivo x-ray computed tomography angiography. Methods: Cell-seeded and unseeded scaffolds were implanted in 5 lambs as inferior vena cava interposition grafts. At 2 and 6 months after implantation, in vivo angiography was used to assess graft morphology. In vivo and ex vivo single photon emission tomography/computed tomography imaging was performed with a radiolabeled compound targeting matrix metalloproteinase activity at 6 months. The neotissue was examined at 6 months using qualitative histologic and immunohistochemical staining and quantitative biochemical analysis. Results: The seeded grafts demonstrated significant luminal and longitudinal growth from 2 to 6 months. In vivo imaging revealed subjectively greater matrix metalloproteinase activity in grafts versus native tissue. Ex vivo imaging confirmed a quantitative increase in matrix metalloproteinase activity and demonstrated greater activity in unseeded versus seeded grafts. The glycosaminoglycan content was increased in seeded grafts versus unseeded grafts, without significant differences in collagen content. Conclusions: Matrix metalloproteinase activity remained elevated in tissue-engineered grafts 6 months after implantation and could indicate remodeling. Optimization of in vivo imaging to noninvasively evaluate matrix metalloproteinase activity could assist in the serial assessment of vascular graft remodeling.